Sekundäre Neuroprotektion beim Glaukom durch ergänzende medikamentöse Therapiekonzepte

Zusammenfassung

Das primäre Offenwinkelglaukom (POWG) wird derzeit als eine neurodegenerative Systemerkrankung angesehen. Die alleinige individualisierte Augeninnendrucksenkung wird dabei dem komplexen Geschehen im chronischen Verlauf der Erkrankung nicht gerecht werden, sodass begleitende medikamentöse Therapiekonzepte sinnvoll sind. Anhand von 4 Therapiestrategien, wie die Verbesserung der mitochondrialen Atmungskette mit Coenzym Q10, die Stabilisierung der mitochondrialen und zellulären Plasmamembranen mit Citicolin, die Verminderung des oxidativen Stresses am Auge und im Körper mit Curcumin und die Verbesserung des Fettstoffwechsels, speziell des LDL-Cholesterins, mit der Anwendung der Statine, soll ein Einblick in mögliche additive Therapieansätze gegeben werden. Da neuroprotektive Therapien als Monotherapien wenig erfolgversprechend sein dürften, werden sie eher in der Kombination aus verschiedenen Therapieansätzen bestehen.

Abstract

Primary open angle glaucoma (POAG) is currently considered a neurodegenerative systemic disease. The individualised reduction in intraocular pressure alone does not do justice to the complex events in the chronic course of the disease, so that accompanying drug therapy concepts are useful. Based on four therapeutic strategies, such as the improvement of the mitochondrial respiratory chain with coenzyme Q10, the stabilisation of the mitochondrial and cellular plasma membranes with citicoline, the reduction in oxidative stress in the eye and in the body with curcumin and the improvement of fat metabolism, especially LDL cholesterol, with the application of statins, an insight into possible additive therapeutic approaches will be provided. Since neuroprotective therapies as monotherapies are unlikely to be very promising, they are more likely to consist of a combination of different therapeutic approaches.

Schlüsselwörter

Glaukom - Neurodegeneration - Coenzym Q10 - Citicolin - Curcumin - Statine

Key words

glaucoma - neurodegeneration - coenzyme Q10 - citicoline - curcumin - statins

• Literatur

• 1 European Glaucoma Society. Terminology and guidelines for glaucoma. 4th ed. Savona: SvetPrint; 2014
• 2 Tham YC, Li X, Wong TY. et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: systemic review and meta-analysis. Ophthalmology 2014; 121: 2081-2090
• 3 Pascolini D, Mariotti SP. Global estimates of visual impairment: 2010. Br J Ophthalmol 2012; 96: 614-618
• 4 McMonnies CW. Glaucoma history and risk factors. J Optom 2017; 10: 71-78
• 5 Wey S, Amanullah S, Spaeth GL. et al. Is primary open-angle glaucoma an ocular manifestation of systemic disease?. Graefes Arch Clin Exp Ophthalmol 2019; 257: 665-673
• 6 Gupta N, Ang LC, Noël de Tilly L. et al. Human glaucoma and neural degeneration in intracranial optic nerve, lateral geniculate nucleus, and visual cortex. Br J Ophthalmol 2006; 90: 674-678
• 7 Gupta N, Ly T, Zhang Q. et al. Chronic ocular hypertension induces dendrite pathology in the lateral geniculate nucleus of the brain. Exp Eye Res 2007; 84: 176-184
• 8 Michelson G, Wärntges S, Engelhorn T. et al. Integrität/Demyelinisierung der Radiatio optica, Morphologie der Papille und Kontrastsensitivität bei Glaukompatienten. Klin Monatsbl Augenheilkd 2012; 229: 143-148
• 9 Nuzzi R, Dallorto L, Rolle T. Changes of Visual Pathway and Brain Connectivity in Glaucoma: A Systematic Review. Front Neurosci 2018; 12: 363 doi:10.3389/fnins.2018.00363
• 10 Abu-Amero KK, Morales J, Bosley TM. Mitochondrial abnormalities in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci 2006; 47: 2533-2541
• 11 Erb C, Konieczka K. Mitochondrial Dysfunctions and Role of Coenzyme Q10 in Patients with Glaucoma. Klin Monatsbl Augenheilkd 2018; 235: 157-162
• 12 Osborne NN. Mitochondria: Their role in ganglion cell death and survival in primary open angle glaucoma. Exp Eye Res 2010; 90: 750-757
• 13 Khawaja AP, Cooke Bailey JN, Kang JH. et al. Assessing the Association of Mitochondrial Genetic Variation With Primary Open-Angle Glaucoma Using Gene-Set Analyses. Invest Ophthalmol Vis Sci 2016; 57: 5046-5052
• 14 Roca-Agujetas V, de Dios C, Lestón L. et al. Recent Insights into the Mitochondrial Role in Autophagy and Its Regulation by Oxidative Stress. Oxid Med Cell Longev 2019; 2019: 3809308 doi:10.1155/2019/3809308
• 15 Guo Y, Chen X, Zhang H. et al. Association of OPA1 polymorphisms with NTG and HTG: a meta-analysis. PLoS One 2012; 7: e42387 doi:10.1371/journal.pone.0042387
• 16 Olichon A, Guillou E, Delettre C. et al. Mitochondrial dynamics and disease, OPA1. Biochim Biophys Acta 2006; 1763: 500-509
• 17 Pawlikowska P, Orzechowski A. Role of transmembrane GTPases in mitochondrial morphology and activity. Postepy Biochem 2007; 53: 53-59
• 18 Abu-Amero KK, Kondkar AA, Chalam KV. Mitochondrial aberrations and ophthalmic diseases. J Transl Sci 2016; 3: 1-11
• 19 Fourgeux C, Martine L, Björkhem I. et al. Primary open-angle glaucoma: association with cholesterol 24S-hydroxylase (CYP46A1) gene polymorphism and plasma 24-hydroxycholesterol levels. Invest Ophthalmol Vis Sci 2009; 50: 5712-5717
• 20 Ren H, Magulike N, Ghebremeskel K. et al. Primary open-angle glaucoma patients have reduced levels of blood docosahexaenoic and eicosapentaenoic acids. Prostaglandins Leukot Essent Fatty Acids 2006; 74: 157-163
• 21 Winder AF. Circulating lipoprotein and blood glucose levels in association with low-tension and chronic simple glaucoma. Br J Ophthalmol 1977; 61: 641-645
• 22 Tanaka C, Yamazaki Y, Yokoyama H. Study on the Progression of Visual Field Defect and Clinical Factors in Normal-Tension Glaucoma. Jpn J Ophthalmol 2001; 45: 117
• 23 Lin HC, Chien CW, Hu CC. et al. Comparison of comorbid conditions between open-angle glaucoma patients and a control cohort: a case-control study. Ophthalmology 2010; 117: 2088-2095
• 24 Modrzejewska M, Grzesiak W, Zaborski D. et al. The Role of Lipid Dysregulation and Vascular Risk Factors in Glaucomatous Retrobulbar Circulation. Bosn J Basic Med Sci 2015; 15: 50-56
• 25 Lane-Donovan C, Philips GT, Herz J. More Than Cholesterol Transporters: Lipoprotein Receptors in CNS Function and Neurodegeneration. Neuron 2014; 83: 771-787
• 26 Chang IL, Elner G, Yue YJ. et al. Expression of modified low-density lipoprotein receptors by trabecular meshwork cells. Curr Eye Res 1991; 10: 1101-1112
• 27 Song CY, Kim BC, Hong HK. et al. Oxidized LDL activates PAI-1 transcription through autocrine activation of TGF-beta signaling in mesangial cells. Kidney Int 2005; 67: 1743-1752
• 28 Meyer MW, von Depka M, Wilhelm C. et al. Plasminogen activator inhibitor-1 mRNA expression in cultured pigmented ciliary epithelial cells of the porcine eye. Graefes Arch Clin Exp Ophthalmol 2002; 240: 679-686
• 29 Fuchshofer R, Welge-Lussen U, Lütjen-Drecoll E. The effect of TGF-beta2 on human trabecular meshwork extracellular proteolytic system. Exp Eye Res 2003; 77: 757-765
• 30 Zode GS, Clark AF, Wordinger RJ. Bone morphogenetic protein 4 inhibits TGF-beta2 stimulation of extracellular matrix proteins in optic nerve head cells: role of gremlin in ECM modulation. Glia 2009; 57: 755-766
• 31 Dan J, Belyea D, Gertner G. et al. Plasminogen activator inhibitor-1 in the aqueous humor of patients with and without glaucoma. Arch Ophthalmol 2005; 123: 220-224
• 32 Jünemann A, Rejdak R, Hohberger B. Significance of Homocysteine in Glaucoma. Klin Monatsbl Augenheilkd 2018; 235: 163-174
• 33 Brandt F, Thvilum M, Hegedüs L. et al. Hyperthyroid patients without Gravesʼ orbitopathy are not at increased risk of developing glaucoma: a nationwide Danish register-based case-control study. Endocrine 2018; 59: 137-142
• 34 Kim JW, Ko J, Woo YJ. et al. Prevalence of Ocular Hypertension and Glaucoma as Well as Associated Factors in Gravesʼ Orbitopathy. J Glaucoma 2018; 27: 464-469
• 35 Haefliger IO, von Arx G, Pimentel AR. Pathophysiology of intraocular pressure increase and glaucoma prevalence in thyroid eye disease: a mini-review. Klin Monatsbl Augenheilkd 2010; 227: 292-293
• 36 Wang S, Liu Y, Zheng G. Hypothyroidism as a risk factor for open angle glaucoma: A systematic review and meta-analysis. PLoS One 2017; 12: e0186634
• 37 Smith KD, Tevaarwerk GJ, Allen LH. An ocular dynamic study supporting the hypothesis that hypothyroidism is a treatable cause of secondary open-angle glaucoma. Can J Ophthalmol 1992; 27: 341-344
• 38 Stein R, Romano A, Treister G. et al. Effect of subconjunctival injection of hyaluronidase on outflow resistance in normal and in open-angle glaucomatous patients. Metab Pediatr Syst Ophthalmol 1982; 6: 169-174
• 39 Duncan KG, Jumper MD, Ribeiro RC. et al. Human trabecular meshwork cells as a thyroid hormone target tissue: presence of functional thyroid hormone receptors. Graefes Arch Clin Exp Ophthalmol 1999; 237: 231-240
• 40 Grieshaber MC, Flammer J. Does the blood-brain barrier play a role in Glaucoma?. Surv Ophthalmol 2007; 52 (Suppl. 02) S115-S121
• 41 Carreras FJ. Lessons From Glaucoma: Rethinking the Fluid-Brain Barriers in Common Neurodegenerative Disorders. Neural Regen Res 2019; 14: 962-966
• 42 Sweeney MD, Zhao Z, Montagne A. et al. Blood-Brain Barrier: From Physiology to Disease and Back. Physiol Rev 2019; 99: 21-78
• 43 Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 2018; 14: 133-150
• 44 Criscuolo C, Fabiani C, Cerri E. et al. Synaptic Dysfunction in Alzheimerʼs Disease and Glaucoma: From Common Degenerative Mechanisms Toward Neuroprotection. Front Cell Neurosci 2017; 11: 53 doi:10.3389/fncel.2017.00053
• 45 Lam DM. Neurotransmitters in the vertebrate retina. Invest Ophthalmol Vis Sci 1997; 38: 553-556
• 46 Massey SC, Redburn DA. Transmitter circuits in the vertebrate retina. Prog Neurobiol 1987; 28: 55-96
• 47 Nicholls D, Attwell D. The release and uptake of excitatory amino acids. Trends Pharmacol Sci 1990; 11: 462-468
• 48 Puyal J, Ginet V, Clarke PG. Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: a challenge for neuroprotection. Prog Neurobiol 2013; 105: 24-48
• 49 Sucher NJ, Lipton SA, Dreyer EB. Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res 1997; 37: 3483-3493
• 50 Malik AR, Willnow TE. Excitatory Amino Acid Transporters in Physiology and Disorders of the Central Nervous System. Int J Mol Sci 2019;
• 51 Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic–ischemic brain damage. Ann Neurol 1986; 19: 105-111
• 52 Vorwerk C. Retinale Exzitotoxizität und Glaukom. In: Erb C, Arend O. Hrsg. Neuronale Konzepte beim Glaukom. Bremen: Uni-Med; 2005: 74-82
• 53 Seki M, Lipton SA. Targeting excitotoxic/free radical signaling pathways for therapeutic intervention in glaucoma. Prog Brain Res 2008; 173: 495-510
• 54 Hynd MR, Scott HL, Dodd PR. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimerʼs disease. Neurochem Int 2004; 45: 583-595
• 55 Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 2010; 460: 525-542
• 56 Berdahl JP, Fautsch MP, Stinnett SS. et al. Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study. Invest Ophthalmol Vis Sci 2008; 49: 5412-5418
• 57 Jonas JB, Wang N, Yang D. et al. Facts and myths of cerebrospinal fluid pressure for the physiology of the eye. Prog Retin Eye Res 2015; 46: 67-83
• 58 Plog BA, Nedergaard M. The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future. Annu Rev Pathol 2018; 13: 379-394
• 59 Mathieu E, Gupta N, Ahari A. et al. Evidence for Cerebrospinal Fluid Entry Into the Optic Nerve via a Glymphatic Pathway. Invest Ophthalmol Vis Sci 2017; 58: 4784-4791
• 60 Nagelhus EA, Ottersen OP. Physiological roles of aquaporin-4 in brain. Physiol Rev 2013; 93: 1543-1562
• 61 Verheggen ICM, Van Boxtel MPJ, Verhey FRJ. et al. Interaction between blood-brain barrier and glymphatic system in solute clearance. Neurosci Biobehav Rev 2018; 90: 26-33
• 62 Ueno M, Chiba Y, Murakami R. et al. Disturbance of Intracerebral Fluid Clearance and Blood-Brain Barrier in Vascular Cognitive Impairment. Int J Mol Sci 2019;
• 63 Wostyn P, Van Dam D, Audenaert K. et al. A new glaucoma hypothesis: a role of glymphatic system dysfunction. Fluids Barriers CNS 2015; 12: 16 doi:10.1186/s12987-015-0012-z
• 64 Mathieu E, Gupta N, Paczka-Giorgi LA. et al. Reduced Cerebrospinal Fluid Inflow to the Optic Nerve in Glaucoma. Invest Ophthalmol Vis Sci 2018; 59: 5876-5884
• 65 Killer HE, Miller NR, Flammer J. et al. Cerebrospinal fluid exchange in the optic nerve in normal-tension glaucoma. Br J Ophthalmol 2012; 96: 544-548
• 66 Killer HE. Compartment syndromes of the optic nerve and open-angle glaucoma. J Glaucoma 2013; 22 (Suppl. 05) S19-S20
• 67 Kim YK, Nam KI, Song J. The Glymphatic System in Diabetes-Induced Dementia. Front Neurol 2018; 9: 867 doi:10.3389/fneur.2018.00867
• 68 Mestre H, Tithof J, Du T. et al. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat Commun 2018; 9: 4878 doi:10.1038/s41467-018-07318-3
• 69 Mortensen KN, Sanggaard S, Mestre H. et al. Impaired Glymphatic Transport in Spontaneously Hypertensive Rats. J Neurosci 2019; 39: 6365-6377
• 70 Buckley C, Hadoke PW, Henry E. et al. Systemic vascular endothelial cell dysfunction in normal pressure glaucoma. Br J Ophthalmol 2002; 86: 227-232
• 71 Fadini GP, Pagano C, Baesso I. et al. Reduced endothelial progenitor cells and brachial artery flow-mediated dilation as evidence of endothelial dysfunction in ocular hypertension and primary open-angle glaucoma. Acta Ophthalmol 2010; 88: 135-141
• 72 Gugleta K. Significance of Endothelin-1 in Glaucoma – a Short Overview. Klin Monatsbl Augenheilkd 2018; 235: 140-145
• 73 Haefliger IO, Dettmann E, Liu R. et al. Potential role of nitric oxide and endothelin in the pathogenesis of glaucoma. Surv Ophthalmol 1999; 43 (Suppl. 01) S51-S58
• 74 Lenin R, Thomas SM, Gangaraju R. Endothelial Activation and Oxidative Stress in Neurovascular Defects of the Retina. Curr Pharm Des 2018; 24: 4742-4754
• 75 Kaur R, Kaur M, Singh J. Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: molecular insights and therapeutic strategies. Cardiovasc Diabetol 2018; 17: 121
• 76 Potenza MA, Gagliardi S, Nacci C. et al. Endothelial dysfunction in diabetes: from mechanisms to therapeutic targets. Curr Med Chem 2009; 16: 94-112
• 77 Konukoglu D, Uzun H. Endothelial Dysfunction and Hypertension. Adv Exp Med Biol 2017; 956: 511-540
• 78 Muoio V, Persson PB, Sendeski MM. The neurovascular unit – concept review. Acta Physiol (Oxf) 2014; 210: 790-798
• 79 Presta I, Vismara M, Novellino F. et al. Innate Immunity Cells and the Neurovascular Unit. Int J Mol Sci 2018;
• 80 Cai W, Zhang K, Li P. et al. Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect. Ageing Res Rev 2017; 34: 77-87
• 81 Iadecola C. The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron 2017; 96: 17-42
• 82 Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843-854
• 83 Xie X, Lu J, Kulbokas EJ. et al. Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals. Nature 2005; 434: 338-345
• 84 Juźwik CA, Drake SS, Zhang Y. et al. microRNA dysregulation in neurodegenerative diseases: A systematic review. Prog Neurobiol 2019; 182: 101664 doi:10.1016/j.pneurobio.2019.101664
• 85 Guo R, Shen W, Su C. et al. Relationship between the Pathogenesis of Glaucoma and miRNA. Ophthalmic Res 2017; 57: 194-199
• 86 Molasy M, Walczak A, Szaflik J. et al. MicroRNAs in glaucoma and neurodegenerative diseases. J Hum Genet 2017; 62: 105-112
• 87 Wang X, Li Z, Bai J. et al. miR-17-5 p regulates the proliferation and apoptosis of human trabecular meshwork cells by targeting phosphatase and tensin homolog. Mol Med Rep 2019; 19: 3132-3138
• 88 Liu Y, Wang Y, Chen Y. et al. Discovery and Validation of Circulating Hsa-miR-210–3 p as a Potential Biomarker for Primary Open-Angle Glaucoma. Invest Ophthalmol Vis Sci 2019; 60: 2925-2934
• 89 Li X, Wang Q, Ren Y. et al. Tetramethylpyrazine protects retinal ganglion cells against H2O2-induced damage via the microRNA-182/mitochondrial pathway. Int J Mol Med 2019; 44: 503-512
• 90 Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science 2016; 353: 777-783
• 91 Chen WW, Zhang X, Huang WJ. Role of neuroinflammation in neurodegenerative diseases. Mol Med Rep 2016; 13: 3391-3396
• 92 Xu L, He D, Bai Y. Microglia-Mediated Inflammation and Neurodegenerative Disease. Mol Neurobiol 2016; 53: 6709-6715
• 93 Hickman S, Izzy S, Sen P. et al. Microglia in neurodegeneration. Nat Neurosci 2018; 21: 1359-1369
• 94 Williams PA, Marsh-Armstrong N, Howell GR. Lasker/IRRF Initiative on Astrocytes and Glaucomatous Neurodegeneration Participants. Neuroinflammation in glaucoma: A new opportunity. Exp Eye Res 2017; 157: 20-27 doi:10.1016/j.exer.2017.02.014
• 95 Wei X, Cho KS, Thee EF. et al. Neuroinflammation and microglia in glaucoma: time for a paradigm shift. J Neurosci Res 2019; 97: 70-76
• 96 Adornetto A, Russo R, Parisi V. Neuroinflammation as a target for glaucoma therapy. Neural Regen Res 2019; 14: 391-394
• 97 Benoist dʼAzy C, Pereira B, Chiambaretta F. et al. Oxidative and Anti-Oxidative Stress Markers in Chronic Glaucoma: A Systematic Review and Meta-Analysis. PLoS One 2016; 11: e0166915
• 98 Kumar DM, Agarwal N. Oxidative stress in glaucoma: a burden of evidence. J Glaucoma 2007; 16: 334-343
• 99 Erb C, Heinke M. Oxidative stress in primary open-angle glaucoma. Front Biosci (Elite Ed) 2011; 3: 1524-1533
• 100 Liu T, Zhang L, Joo D. et al. NF-κB signaling in inflammation. Signal Transduct Target Ther 2017;
• 101 Erb C. Importance of the nuclear factor kappaB for the primary open angle glaucoma–a hypothesis. Klin Monatsbl Augenheilkd 2010; 227: 120-127
• 102 Takahashi Y, Katai N, Murata T. et al. Development of spontaneous optic neuropathy in NF-kappaBetap50-deficient mice: requirement for NF-kappaBetap50 in ganglion cell survival. Neuropathol Appl Neurobiol 2007; 33: 692-705
• 103 Swarup G, Sayyad Z. Altered Functions and Interactions of Glaucoma-Associated Mutants of Optineurin. Front Immunol 2018; 9: 1287 doi:10.3389/fimmu.2018.01287
• 104 Alexopoulos H, Dalakas MC. The immunobiology of autoimmune encephalitides. J Autoimmun 2019; 104: 102339 doi:10.1016/j.jaut.2019.102339
• 105 Wesselingh R, Butzkueven H, Buzzard K. et al. Innate Immunity in the Central Nervous System: A Missing Piece of the Autoimmune Encephalitis Puzzle?. Front Immunol 2019; 10: 2066 doi:10.3389/fimmu.2019.02066
• 106 Zitti B, Bryceson YT. Natural killer cells in inflammation and autoimmunity. Cytokine Growth Factor Rev 2018; 42: 37-46
• 107 Cusick MF, Libbey JE, Fujinami RS. Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol 2012; 42: 102-111
• 108 Tsolaki F, Kountouras J, Topouzis F. et al. Helicobacter pylori infection, dementia and primary open-angle glaucoma: are they connected?. BMC Ophthalmol 2015; 15: 24
• 109 Joachim SC. Significance of Helicobacter pylori Diagnostic in Glaucoma. Klin Monatsbl Augenheilkd 2018; 235: 135-139
• 110 Wax MB. The case for autoimmunity in glaucoma. Exp Eye Res 2011; 93: 187-190
• 111 Grus FH, Gramlich OW. Autoimmunity and glaucoma. Klin Monatsbl Augenheilkd 2011; 228: 439-445
• 112 Bell K, Gramlich OW, Von Thun Und Hohenstein-Blaul N. et al. Does autoimmunity play a part in the pathogenesis of glaucoma?. Prog Retin Eye Res 2013; 36: 199-216
• 113 Bell K, Funke S, Grus FH. Autoimmunity and glaucoma. Ophthalmologe 2019; 116: 18-27
• 114 Erb C. Wie läuft die Entstehung und Progression eines Optikusschadens bei einem primären Offenwinkelglaukom ab und welche Bedeutung haben diese Erkenntnisse für die Glaukomdiagnostik?. Klin Monatsbl Augenheilkd 2012; 229: 106-111
• 115 Porciatti V, Ventura LM. Retinal ganglion cell functional plasticity and optic neuropathy: a comprehensive model. J Neuroophthalmol 2012; 32: 354-358
• 116 Mardin CY. Die wichtigsten ophthalmologischen Papillenveränderungen bei den Glaukomen. Klin Monatsbl Augenheilkd 2012; 229: 112-118
• 117 Grewal DS, Tanna AP. Diagnosis of glaucoma and detection of glaucoma progression using spectral domain optical coherence tomography. Curr Opin Ophthalmol 2013; 24: 150-161
• 118 Erb C, Göbel K. Functional glaucoma diagnosis. Ophthalmologe 2009; 106: 375-385
• 119 Katsnelson A, De Strooper B, Zoghbi HY. Neurodegeneration: From cellular concepts to clinical applications. Sci Transl Med 2016; 8: 364ps18
• 120 Rüfer F. Sekundäre Neuroprotektion beim Glaukom durch Lebensstiländerungen. Klin Monatsbl Augenheilkd 2020;
• 121 Hacke C, Erb C, Weisser B. Risikofaktoren und Zielwerte in der kardiovaskulären Primär- und Sekundärprävention: Bedeutung für das Glaukom. Klin Monatsbl Augenheilkd 2018; 235: 151-156
• 122 Turunen M, Olsson J, Dallner G. Metabolismand function of coenzyme Q. Biochim Biophys Acta 2004; 1660: 171-199
• 123 Qu J, Kaufman Y, Washington I. Coenzyme Q10 in the human retina. Invest Ophthalmol Vis Sci 2009; 50: 1814-1818
• 124 Qu J, Ma L, Washington I. Retinal coenzyme Q10 in the bovine eye. Biofactors 2011; 37: 393-398
• 125 Lulli M, Witort E, Papucci L. et al. Coenzyme Q10 instilled as eye drops on the cornea reaches the retina and protects retinal layers from apoptosis in a mouse model of kainate-induced retinal damage. Invest Ophthalmol Vis Sci 2012; 53: 8295-8302
• 126 Lee D, Shim MS, Kim KY. et al. Coenzyme Q10 inhibits glutamate excitotoxicity and oxidative stress-mediated mitochondrial alteration in a mouse model of glaucoma. Invest Ophthalmol Vis Sci 2014; 55: 993-1005
• 127 Nucci C, Tartaglione R, Cerulli A. et al. Retinal damage caused by high intraocular pressure-induced transient ischemia is prevented by coenzyme Q10 in rat. Int Rev Neurobiol 2007; 82: 397-406
• 128 Davis BM, Tian K, Pahlitzsch M. et al. Topical coenzyme Q10 demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension. Mitochondrion 2017; 36: 114-123
• 129 Nakajima Y, Inokuchi Y, Nishi M. et al. Coenzyme Q10 protects retinal cells against oxidative stress in vitro and in vivo. Brain Res 2008; 1226: 226-233
• 130 Noh YH, Kim KY, Shim MS. et al. Inhibition of oxidative stress by coenzyme Q10 increases mitochondrial mass and improves bioenergetic function in optic nerve head astrocytes. Cell Death Dis 2013; 4: e820 doi:10.1038/cddis.2013.341
• 131 Jing L, He MT, Chang Y. et al. Coenzyme Q10 protects astrocytes from ROS-induced damage through inhibition of mitochondria-mediated cell death pathway. Int J Biol Sci 2015; 11: 59-66
• 132 Parisi V, Centofanti M, Gandolfi S. et al. Effects of coenzyme Q10 in conjunction with vitamin E on retinal-evoked and cortical-evoked responses in patients with open-angle glaucoma. J Glaucoma 2014; 23: 391-404
• 133 Ozates S, Elgin KU, Yilmaz NS. et al. Evaluation of oxidative stress in pseudo-exfoliative glaucoma patients treated with and without topical coenzyme Q10 and vitamin E. Eur J Ophthalmol 2019; 29: 196-201
• 134 Hargreaves IP. Coenzyme Q10 as a therapy for mitochondrial disease. Int J Biochem Cell Biol 2014; 49: 105-111
• 135 Orsucci D, Mancuso M, Ienco EC. et al. Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues. Curr Med Chem 2011; 18: 4053-4064
• 136 Yang X, Zhang Y, Xu H. et al. Neuroprotection of Coenzyme Q10 in Neurodegenerative Diseases. Curr Top Med Chem 2016; 16: 858-866
• 137 Lulli M, Witort E, Papucci L. et al. Coenzyme Q10 instilled as eye drops on the cornea reaches the retina and protects retinal layers from apoptosis in a mouse model of kainate-induced retinal damage. Invest Ophthalmol Vis Sci 2012; 53: 8295-8302
• 138 Fato R, Bergami C, Leoni S. et al. Coenzyme Q10 vitreous levels after administration of coenzyme Q10 eyedrops in patients undergoing vitrectomy. Acta Ophthalmol 2010; 88: e150
• 139 Hyun DH. Plasma membrane redox enzymes: new therapeutic targets for neurodegenerative diseases. Arch Pharm Res 2019; 42: 436-445
• 140 Pavel M, Rubinsztein DC. Mammalian autophagy and the plasma membrane. FEBS J 2017; 284: 672-679
• 141 Zemirli N, Morel E, Molino D. Mitochondrial Dynamics in Basal and Stressful Conditions. Int J Mol Sci 2018;
• 142 Radak Z, Zhao Z, Goto S. et al. Age-associated neurodegeneration and oxidative damage to lipids, proteins and DNA. Mol Aspects Med 2011; 32: 305-315
• 143 Indiveri C, Iacobazzi V, Tonazzi A. et al. The mitochondrial carnitine/acylcarnitine carrier: function, structure and physiopathology. Mol Aspects Med 2011; 32: 223-233
• 144 Secades JJ. Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol 2016; 63: S1-S73
• 145 Rao AM, Hatcher JF, Dempsey RJ. CDP-choline: neuroprotection in transient forebrain ischemia of gerbils. J Neurosci Res 1999; 58: 697-705
• 146 Skripuletz T, Manzel A, Gropengießer K. et al. Pivotal role of choline metabolites in remyelination. Brain 2015; 138: 398-413
• 147 Silveri MM, Dikan J, Ross AJ. et al. Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy. NMR Biomed 2008; 21: 1066-1075
• 148 Babb SM, Wald LL, Cohen BM. et al. Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study. Psychopharmacology (Berl) 2002; 161: 248-254
• 149 Dávalos A, Castillo J, Alvarez-Sabín J. et al. Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Stroke 2002; 33: 2850-2857
• 150 Overgaard K. The effects of citicoline on acute ischemic stroke: a review. J Stroke Cerebrovasc Dis 2014; 23: 1764-1769
• 151 Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev 2005; (18) CD000269
• 152 Grieb P, Jünemann A, Rekas M. et al. Citicoline: A Food Beneficial for Patients Suffering from or Threated with Glaucoma. Front Aging Neurosci 2016; 8: 73
• 153 Iulia C, Ruxandra T, Costin LB. et al. Citicoline – a neuroprotector with proven effects on glaucomatous disease. Rom J Ophthalmol 2017; 61: 152-158
• 154 Schuettauf F, Rejdak R, Thaler S. et al. Citicoline and lithium rescue retinal ganglion cells following partial optic nerve crush in the rat. Exp Eye Res 2006; 83: 1128-1134
• 155 Parisi V, Manni G, Colacino G. et al. Cytidine-5′-diphosphocholine (citicoline) improves retinal and cortical responses in patients with glaucoma. Ophthalmology 1999; 106: 1126-1134
• 156 Parisi V, Coppola G, Centofanti M. et al. Evidence of the neuroprotective role of citicoline in glaucoma patients. Prog Brain Res 2008; 173: 541-554
• 157 Virno M, Pecori-Giraldi J, Liguori A. et al. The protective effect of citicoline on the progression of the perimetric defects in glaucomatous patients (perimetric study with a 10-year follow-up). Acta Ophthalmol Scand Suppl 2000; 232: 56-57
• 158 Ottobelli L, Manni GL, Centofanti M. et al. Citicoline oral solution in glaucoma: is there a role in slowing disease progression?. Ophthalmologica 2013; 229: 219-226
• 159 Parisi V, Centofanti M, Ziccardi L. et al. Treatment with citicoline eye drops enhances retinal function and neural conduction along the visual pathways in open angle glaucoma. Graefes Arch Clin Exp Ophthalmol 2015; 253: 1327-1340
• 160 Nelson KM, Dahlin JL, Bisson J. et al. The Essential Medicinal Chemistry of Curcumin. J Med Chem 2017; 60: 1620-1637
• 161 Shoba G, Joy D. et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 1998; 64: 353-356
• 162 Menon VP, Sudheer AR. Antioxidant and anti-inflammatory properties of curcumin. Adv Exp Med Biol 2007; 595: 105-125
• 163 Forouzanfar F, Read MI, Barreto GE. et al. Neuroprotective effects of curcumin through autophagy modulation. IUBMB Life 2019;
• 164 Hu S, Maiti P, Ma Q. et al. Clinical development of curcumin in neurodegenerative disease. Expert Rev Neurother 2015; 15: 629-637
• 165 Concetta Scuto M, Mancuso C, Tomasello B. et al. Curcumin, Hormesis and the Nervous System. Nutrients 2019;
• 166 Abrahams S, Haylett WL, Johnson G. et al. Antioxidant effects of curcumin in models of neurodegeneration, aging, oxidative and nitrosative stress: A review. Neuroscience 2019; 406: 1-21
• 167 Panahi Y, Hosseini MS, Khalili N. Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: A post-hoc analysis of a randomized controlled trial. Biomed Pharmacother 2016; 82: 578-582
• 168 Burugula B, Ganesh BS, Chintala SK. Curcumin attenuates staurosporine-mediated death of retinal ganglion cells. Invest Ophthalmol Vis Sci 2011; 52: 4263-4273
• 169 Xu Y, Ku B, Cui L. et al. Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats. Brain Res 2007; 1162: 9-18
• 170 Wu A, Ying Z, Gomez-Pinilla F. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp Neurol 2006; 197: 309-317
• 171 Shen T, You Y, Joseph C. et al. BDNF Polymorphism: A Review of Its Diagnostic and Clinical Relevance in Neurodegenerative Disorders. Aging Dis 2018; 9: 523-536
• 172 Wang L, Li C, Guo H, Kern TS, Huang K, Zheng L. Curcumin inhibits neuronal and vascular degeneration in retina after ischemia and reperfusion injury. PLoS One 2011; 6: e23194 doi:10.1371/journal.pone.0023194
• 173 Panahi Y, Hosseini MS, Khalili N. Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: A post-hoc analysis of a randomized controlled trial. Biomed Pharmacother 2016; 82: 578-582
• 174 Matteucci A, Cammarota R, Paradisi S. et al. Curcumin protects against NMDA-induced toxicity: a possible role for NR2A subunit. Invest Ophthalmol Vis Sci 2011; 52: 1070-1077
• 175 Mallozzi C, Parravano M, Gaddini L. et al. Curcumin Modulates the NMDA Receptor Subunit Composition Through a Mechanism Involving CaMKII and Ser/Thr Protein Phosphatases. Cell Mol Neurobiol 2018; 38: 1315-1320
• 176 Wang TY, Chen JX. Effects of Curcumin on Vessel Formation Insight into the Pro- and Antiangiogenesis of Curcumin. Evid Based Complement Alternat Med 2019; 2019: 1390795 doi:10.1155/2019/1390795
• 177 Lin C, Wu X. Curcumin Protects Trabecular Meshwork Cells From Oxidative Stress. Invest Ophthalmol Vis Sci 2016; 57: 4327-4332
• 178 Davis BM, Pahlitzsch M, Guo L. et al. Topical Curcumin Nanocarriers are Neuroprotective in Eye Disease. Sci Rep 2018; 8: 11066 doi:10.1038/s41598-018-29393-8
• 179 Radomska-Leśniewska DM, Osiecka-Iwan A, Hyc A. et al. Therapeutic potential of curcumin in eye diseases. Cent Eur J Immunol 2019; 44: 181-189
• 180 Pescosolido N, Giannotti R, Plateroti AM. et al. Curcumin: therapeutical potential in ophthalmology. Planta Med 2014; 80: 249-254
• 181 Kim DS, Kim JY, Han Y. Curcuminoids in neurodegenerative diseases. Recent Pat CNS Drug Discov 2012; 7: 184-204
• 182 Jünemann AG, Huchzermeyer C, Rejdak R. et al. Dyslipidaemia and glaucoma. Klin Monatsbl Augenheilkd 2014; 231: 1203-1214
• 183 Rosenson RS, Hegele RA, Koenig W. Cholesterol-Lowering Agents. Circ Res 2019; 124: 364-385
• 184 Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res 2017; 120: 229-243
• 185 Zhou Q, Liao JK. Pleiotropic effects of statins. – Basic research and clinical perspectives. Circ J 2010; 74: 818-826
• 186 Shahbaz SK, Sadeghi M, Koushki K. et al. Regulatory T cells: Possible mediators for the anti-inflammatory action of statins. Pharmacol Res 2019; 149: 104469 doi:10.1016/j.phrs.2019.104469
• 187 Sironi L, Banfi C, Brioschi M. et al. Activation of NF-kB and ERK1/2 after permanent focal ischemia is abolished by simvastatin treatment. Neurobiol Dis 2006; 22: 445-451
• 188 Kim YS, Ahn Y, Hong MH. et al. Rosuvastatin suppresses the inflammatory responses through inhibition of c-Jun N-terminal kinase and nuclear factor-kappaB in endothelial cells. J Cardiovasc Pharmacol 2007; 49: 376-383
• 189 Stüve O, Youssef S, Steinman L. et al. Statins as potential therapeutic agents in neuroinflammatory disorders. Curr Opin Neurol 2003; 16: 393-401
• 190 Bagheri H, Ghasemi F, Barreto GE. et al. The effects of statins on microglial cells to protect against neurodegenerative disorders: A mechanistic review. Biofactors 2019;
• 191 Puyal J, Ginet V, Clarke PG. Multiple interacting cell death mechanisms in the mediation of excitotoxicity and ischemic brain damage: a challenge for neuroprotection. Prog Neurobiol 2013; 105: 24-48
• 192 Chauhan A, Hahn S, Gartner S. et al. Molecular programming of endothelin-1 in HIV-infected brain: role of Tat in up-regulation of ET-1 and its inhibition by statins. FASEB J 2007; 21: 777-789
• 193 Song J, Deng PF, Stinnett SS. et al. Effects of cholesterol lowering statins on the aqueous humor outflow pathway. Invest Ophthalmol Vis Sci 2005; 46: 2424-2432
• 194 Villarreal jr. G, Chatterjee A, Oh SS. et al. Pharmacological regulation of SPARC by lovastatin in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 2014; 55: 1657-1665
• 195 Nagaoka T, Takahashi A, Sato E. et al. Effect of systemic administration of imvastatin on retinal circulation. Arch Ophthalmol 2006; 124: 665-670
• 196 Honjo M, Tanihara H, Nishijima K. et al. Statin inhibits leukocyte-endothelial interaction and prevents neuronal death induced by ischemia-reperfusion injury in the rat retina. Arch Ophthalmol 2002; 120: 1707-1713
• 197 Ooi KG, Khoo P, Vaclavik V. et al. Statins in ophthalmology. Surv Ophthalmol 2019; 64: 401-432
• 198 Banach M, Stulc T, Dent R. et al. Statin non-adherence and residual cardiovascular risk: There is need for substantial improvement. Int J Cardiol 2016; 225: 184-196
• 199 François Mach, Baigent C, Catapano AL. et al. ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J 2020; 41: 111-188 doi:10.1093/eurheartj/ehz455
• 200 Pache M, Flammer J. A sick eye in a sick body? Systemic findings in patients with primary open-angle glaucoma. Surv Ophthalmol 2006; 51: 179-212
• 201 Meyer R. Statine in stetem Diskurs. Deutsches Ärztebl 2019; 116 (03) A80-A83
• 202 Newman CB, Preiss D, Tobert JA. et al. Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol 2019; 39: e38-e81